Substituted 3,4-diamino-1,2,5-thiadiazoles having histamine H2 -receptor antagonist activity

ABSTRACT

Histamine H 2  -receptor antagonists of the formula ##STR1## wherein A, m, Z, n and R 1  are as defined herein, and their nontoxic pharmaceutically acceptable salts, hydrates and solvates are novel anti-ulcer agents which are prepared by ring closure of a substituted ethanediimidamide of the formula ##STR2##

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of our prior, co-pending applicationSer. No. 473,791, filed Mar. 16, 1983, which is a continuation-in-partof our prior, co-pending application Ser. No. 363,207, filed Mar. 29,1982 now abandoned.

SUMMARY OF THE INVENTION

Certain 3-(amino or substituted amino)-4-(substitutedamino)-1,2,5-thiadiazoles having the formula ##STR3## wherein A, m, Z, nand R¹ are as defined below, and their nontoxic pharmaceuticallyacceptable salts, hydrates and solvates, are potent histamine H₂-receptor antagonists which inhibit gastric acid secretion and areuseful in the treatment of peptic ulcers and other pathologicalhypersecretory conditions. The compounds are prepared by ring closure ofthe correspondingly substituted ethanediimidamide of the formula##STR4## BACKGROUND AND PRIOR ART

Our U.S. Pat. No. 4,374,248, issued Feb. 15, 1983, discloses3,4-disubstituted-1,2,5-thiadiazole 1-oxides and 1,1-dioxides having theformula ##STR5## and processes for their preparation, wherein thevariables A, m, Z, n and R¹ are similar to the correspondingsubstituents of the compounds disclosed and claimed herein. However, thecompounds disclosed therein are 1-oxides or 1,1-dioxides (p is 1 or 2),and the compounds of the present invention cannot be prepared by any ofthe processes described therein for the preparation of the prior artcompounds.

European patent application No. 40,696 published Dec. 2, 1981 disclosesinter alia 3,4-disubstituted-1,2,5-thiadiazole 1-oxides and 1,1-dioxideshaving the formula ##STR6## and processes for their preparation, whereinthe variables R, ○A , n, X, m, R¹ and R² are similar to thecorresponding substituents of the compounds disclosed and claimedherein. However, the compounds disclosed therein also are 1-oxides or1,1-dioxides (p is 1 or 2) and the compounds of the present inventioncannot be prepared by any of the processes described therein for thepreparation of the prior art compounds.

In the two publications cited above, each of the processes described forpreparation of the prior art compounds involves the use (as a startingmaterial or intermediate) of a 1,2,5-thiadiazole 1-oxide or 1,1-dioxidehaving either amino groups or suitable "leaving groups" on the 3- and4-positions. The desired substituents on the 3- and 4-positions are thenobtained by substitution on the amino groups or by replacement of the"leaving groups". We have made extensive attempts to prepare thecompounds of the present invention by similar procedures, i.e. byutilizing 1,2,5-thiadiazole having amino groups or suitable "leavinggroups" on the 3- and 4-positions as starting materials orintermediates. Although numerous variations were tried, along withvarying reaction conditions, we were not able to isolate the compoundsof this invention by that route.

We have now found that the compounds of the present invention may beprepared by ring closure of the correspondingly substitutedethanediimidamide of the formula ##STR7## Intermediate II, itself, maybe prepared by various procedures.

COMPLETE DESCRIPTION

This invention relates to histamine H₂ -receptor antagonists of theformula ##STR8## wherein R¹ is hydrogen, (lower)alkyl, 2-fluoroethyl,2,2,2-trifluoroethyl, allyl, propargyl, ##STR9## in which

p is 1 or 2, R² and R³ each are independently hydrogen, (lower)alkyl,(lower)alkoxy or halogen, and, when R² is hydrogen, R³ also may betrifluoromethyl, or R² and R³, taken together, may be methylenedioxy,and R⁴ is hydrogen, (lower)alkyl or (lower)alkoxy;

m is an integer of from 0 to 2 inclusive;

n is an integer of from 2 to 5 inclusive;

Z is oxygen, sulfur or methylene; and

A is ##STR10## in which R⁵ is hydrogen, (lower)alkyl or (lower)alkoxy, qis an integer of from 1 to 4 inclusive and R⁶ and R⁷ each areindependently (lower)alkyl, (lower)alkoxy(lower)alkyl in which the(lower)alkoxy moiety is at least two carbon atoms removed from thenitrogen atom, or phenyl(lower)alkyl, and, when R⁶ is hydrogen, R⁷ alsomay be cyclo(lower)alkyl, or R⁶ and R⁷, taken together with the nitrogenatom to which they are attached, may be pyrrolidino, methylpyrrolidino,dimethylpyrrolidino, morpholino, thiomorpholino, piperidino,methylpiperidino, dimethylpiperidino, N-methylpiperazino,1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino,octamethyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; andnontoxic, pharmaceutically acceptable salts, hydrates and solvatesthereof.

This invention also relates to processes for the preparation of thecompounds of Formula I and to the intermediate compounds of Formula II.

The present invention includes within its scope all possible tautomericforms, diastereoisomeric forms and optically active isomers of thecompounds of Formula I as well as mixtures thereof. As used herein andin the claims, the term "(lower)alkyl" means a straight or branchedchain alkyl group containing from 1 to 6 carbon atoms. The term"(lower)alkoxy" means a straight or branched chain alkoxy groupcontaining from 1 to 4 carbon atoms. "Cyclo(lower)alkoxy" means acycloalkyl group containing from 3 to 6 carbon atoms. The term "nontoxicpharmaceutically acceptable salts" means acid additon salts formed withacids such as hydrochloric, hydrobromic, nitric, sulfuric, acetic,propionic, fumaric, methanesulfonic, maleic, tartaric, citric,levulinic, benzoic, succinic and the like.

In the compounds of Formula I, R¹ preferably is hydrogen or(lower)alkyl, more preferably is hydrogen or methyl and most preferablyis hydrogen. Substituent A preferably is the substituted phenyl moiety,substituted furyl moiety or substituted thienyl moiety shown above, andmost preferably is the substituted phenyl moiety. Substituent Zpreferably is sulfur or oxygen and, when A is the substituted phenylmoiety, Z preferably is oxygen. It is preferred that m is zero or 1 andn is 2 or 3, and that, when A is the substituted phenyl moiety, m iszero and n is 3. R⁵ preferably is hydrogen or methyl and most preferablyis hydrogen. It is preferred that q is 1. R⁶ and R⁷ preferably are(lower)alkyl or, taken together with the nitrogen atom to which they areattached, are pyrrolidino or piperidino.

The compounds of Formula I may be prepared by reaction of a compound ofFormula II with sulfur monochloride (S₂ Cl₂), sulfur dichloride (SCl₂)or chemical equivalents thereof, as follows: ##STR11## wherein A, m, Z,n and R¹ are as defined above. At least about 1 mole of S₂ Cl₂ or SCl₂should be used per mole of Compound II; it is preferred to use an excessof S₂ Cl₂ or SCl₂, e.g. from about 2 to about 3 moles of S₂ Cl₂ or SCl₂per mole of Compound II. It has been found that SCl₂ often gives acruder product and lower yield of purified product, and we usuallyprefer to use S₂ Cl₂ for the reaction. The reaction temperature is notcritical; we prefer to conduct the reaction at a temperature of fromabout 0° C. to about 50° C., and it is most convenient to conduct thereaction at ambient temperature. The reaction time is not critical andis dependent on temperature. We normally utilize a reaction time of fromabout 30 minutes to about 6 hours. At ambient temperature, reactiontimes of from about 11/2 to 4 hours usually are preferred. The reactionmay be conducted in an inert organic solvent, preferably a mixture of aninert organic solvent and dimethylformamide. Most preferably thereaction is conducted in dimethylformamide.

In a preferred embodiment of the invention, the compounds of Formula Ihave the structure ##STR12## wherein R¹ is hydrogen or (lower)alkyl, mis 0 or 1, n is 2 or 3, Z is oxygen or sulfur and A is ##STR13## inwhich R⁵ is hydrogen or methyl, and R⁶ and R⁷ each are independentlymethyl or ethyl, or when taken together with the nitrogen to which theyare attached, R⁶ and R⁷ represent a pyrrolidino or piperidino ring; or anontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In a more preferred embodiment, the compounds of Formula I have thestructure ##STR14## wherein R¹ is hydrogen or methyl, and R⁶ and R⁷ eachare methyl or, when taken together with the nitrogen atom to which theyare attached, R⁶ and R⁷ represent a pyrrolidino or piperidino ring; or anontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In another more preferred embodiment, the compounds of Formula I havethe structure ##STR15## wherein R¹ and R⁵ each are independentlyhydrogen or methyl, and R⁶ and R⁷ each are independently methyl orethyl; or a nontoxic pharmaceutically acceptable salt, hydrate orsolvate thereof.

In another more preferred embodiment, the compounds of Formula I havethe structure ##STR16## wherein R¹ and R⁵ each are independentlyhydrogen or methyl, and R⁶ and R⁷ each are independently methyl orethyl; or a nontoxic pharmaceutically acceptable salt, hydrate orsolvate thereof.

In another more preferred embodiment, the compounds of Formula I havethe structure ##STR17## wherein R¹ and R⁵ each are independentlyhydrogen or methyl, and R⁶ and R⁷ each are independently methyl orethyl, or, when taken together with the nitrogen to which they areattached, R⁶ and R⁷ represent piperidino; or a nontoxic pharmaceuticallyacceptable salt, hydrate or solvate thereof.

As presently envisaged, the most preferred compounds of Formula I are

[(1)3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(2)3-amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole;

(3)3-amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole,

(4)3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(5)3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(6)3-benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(7)3-amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole,

(8)3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole,

(9)3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazoleand

(10)3-amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole;and their nontoxic, pharmaceutically acceptable salts, hydrates andsolvates.

The intermediates of Formula II used in the preparation of the compoundsof Formula I may themselves be prepared by various procedures. In oneprocedure, the corresponding 3-(amino or substitutedamino)-4-(substituted amino)-1,2,5-thiadiazole 1-oxide of Formula III istreated with a strong mineral acid (preferably HCl) to produce thecompound of Formula II. ##STR18## The reaction may be conducted in aninert solvent and preferably is conducted in methanol. Reactiontemperature is not critical; it most conveniently is conducted at roomtemperature. The compounds of Formula III are known or may readily beprepared by the procedures described in our published U.K. patentapplication No. 2,067,987.

In an alternate procedure, the compounds of Formula II may be preparedby the following reaction scheme. ##STR19## The reaction may beconducted in an inert solvent and preferably is conducted in methanol.The starting materials of Formula IV are known or may be readilyprepared by known procedures, e.g. as by procedures described in ourpublished U.K. patent application No. 2,067,987.

In another aspect, this invention relates to novel intermediates of theformula ##STR20## wherein R¹ is hydrogen, (lower)alkyl, 2-fluoroethyl,2,2,2-trifluoroethyl, allyl, propargyl, ##STR21## in which

p is 1 or 2, R² and R³ each are independently hydrogen, (lower)alkyl,(lower)alkoxy or halogen, and, when R² is hydrogen, R³ also may betrifluoromethyl, or R² and R³, taken together, may be methylenedioxy,and R⁴ is hydrogen, (lower)alkyl or (lower)alkoxy;

m is an integer of from 0 to 2 inclusive;

n is an integer of from 2 to 5 inclusive;

Z is oxygen, sulfur or methylene; and

A is ##STR22## in which R⁵ is hydrogen, (lower)alkyl or (lower)alkoxy, qis an integer of from 1 to 4 inclusive and R⁶ and R⁷ each areindependently (lower)alkyl, (lower)alkoxy(lower)alkyl in which the(lower)alkoxy moiety is at least two carbon atoms removed from thenitrogen atom, or phenyl(lower)alkyl, and, when R⁶ is hydrogen, R⁷ alsomay be cyclo(lower)alkyl, or R⁶ and R⁷, taken together with the nitrogenatom to which they are attached, may be pyrrolidino, methylpyrrolidino,dimethylpyrrolidino, morpholino, thiomorpholino, piperidino,methylpiperidino, dimethylpiperidino, N-methylpiperazino,1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino,octamethyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; or asalt, hydrate or solvate thereof.

In a preferred embodiment, the intermediates of Formula II have thestructure ##STR23## wherein R¹ is hydrogen or (lower)alkyl, m is 0 or 1,n is 2 or 3, Z is oxygen or sulfur and A is ##STR24## in which R⁵ ishydrogen or methyl, and R⁶ and R⁷ each are independently methyl orethyl, or when taken together with the nitrogen to which they areattached, R⁶ and R⁷ represent a pyrrolidino or piperidino ring; or anontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II havethe structure ##STR25## wherein R¹ is hydrogen or methyl, and R⁶ and R⁷each are methyl or, when taken together with the nitrogen atom to whichthey are attached, R⁶ and R⁷ represent a pyrrolidino or piperidino ring;or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II havethe structure ##STR26## wherein R¹ and R⁵ each are independentlyhydrogen or methyl, and R⁶ and R⁷ each are independently methyl orethyl; or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II havethe structure ##STR27## wherein R¹ and R⁵ each are independentlyhydrogen or methyl, and R⁶ and R⁷ each are independently methyl orethyl; or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II havethe structure ##STR28## wherein R¹ and R⁵ each are independentlyhydrogen or methyl, and R⁶ and R⁷ each are independently methyl orethyl, or, when taken together with the nitrogen to which they areattached, R⁶ and R⁷ represent piperidino; or a salt, hydrate or solvatethereof.

As presently envisaged, the most preferred intermediates of Formula IIare

(1) N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide,

(2)N-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethyl}ethanediimidamide,

(3)N-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethyl}ethanediimidamide,

(4) N-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimidamide,

(5)N-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethyl}ethanediimidamide,

(6)N-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethyl}ethanediimidamide,

(7) N-[3-(6-piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamide and

(8) N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamide;

or a salt, hydrate or solvate thereof.

For therapeutic use, the pharmacologically active compounds of Formula Iwill normally be administered as a pharmaceutical composition comprisingas the (or an) essential active ingredient at least one such compound inits basic form or in the form of a nontoxic pharmaceutically acceptableacid addition salt, in association with a pharmaceutically acceptablecarrier.

The pharmaceutical compositions may be administered orally, parenterallyor by rectal suppository. A wide variety of pharmaceutical forms may beemployed. Thus, if a solid carrier is used, the preparation may betableted, placed in a hard gelatin capsule in powder or pellet form, orin the form of a troche or lozenge. If a liquid carrier is employed, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile solution for injection, or an aqueous or non-aqueousliquid suspension. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparation.

The dosage of the compounds of this invention will depend not only onsuch factors as the weight of the patient, but also on the degree ofgastric acid inhibition desired and the potency of the particularcompound being utilized. The decision as to the particular dosage to beemployed (and the number of times to be administered per day) is withinthe discretion of the physician, and may be varied by titration of thedosage to the particular circumstances of the specific patient. With thepreferred compounds of this invention, each oral dosage unit willcontain the active ingredient in an amount of from about 2 mg to about300 mg, and most preferably from about 4 mg to about 100 mg. The activeingredient will preferably be administered in equal doses from one tofour times a day.

Histamine H₂ -receptor antagonists have been shown to be effectiveinhibitors of gastric secretion in animals and man, Brimblecombe et al.,J. Int. Med. Res., 3, 86 (1975). Clinical evaluation of the histamine H₂-receptor antagonist cimetidine has shown it to be an effectivetherapeutic agent in the treatment of peptic ulcer disease, Gray et al.,Lancet, 1, 8001 (1977). Some of the preferred compounds of thisinvention have been compared with cimetidine in various tests and havebeen found to be more potent than cimetidine both as an histamine H₂-receptor antagonist in isolated guinea pig right atria and as aninhibitor of gastric acid secretion in rats and dogs.

Determination of Gastric Antisecretory Activity in the Gastric FistulaRat

Male Long Evans rats weighing about 240-260 grams at the time of cannulaimplantation are used. The design and implanatation of the stainlesssteel cannula into the anterior wall of the fore-stomach are carried outessentially as described by Pare et al. [Laboratory Animal Science, 27,244 (1977)]. The fistula components are designed and the operativeprocedure is carried out exactly as described in the above reference.Post operatively the animals are individually housed in solid bottomcages with sawdust and are allowed food and water ad libitum throughoutthe entire recovery period. Animals are not used for test purposes forat least 15 days after the operative procedure.

The animals are fasted but allowed water ad libitum for 20 hours beforethe testing procedure is to begin. Immediately prior to collection, thecannula is opened and the stomach washed gently with 30-40 mL of warmsaline or distilled water to remove any residual contents. The catheteris then screwed into the cannula in place of the plugging screw and therat is placed in a clear plastic rectangular cage measuring 40 cm long,15 cm wide and 13 cm high. The bottom of the cage has a slitapproximately 1.5 cm wide and 25 cm long running down the center toaccommodate the catheter which hangs through it. In this way the rat isnot restricted and can move freely about the cage during collectionperiods. The remainder of the assay is carried out as described byRidley et al. [Research Comm. Chem. Path. Pharm., 17, 365 (1977)].

Gastric secretions collected during the first hour after washing thestomach are discarded as they may be contaminated. For oral evaluation,the catheter is then removed from the cannula and replaced with theplugging screw. Water (2 mL/kg) is admistered orally via gastricintubation and the animal is returned to the cage for 45 minutes. Afterthis time the plugging screw is removed and replaced with a catheter towhich a small plastic vial has been attached to collect the gastricsecretions. A two-hour sample is collected (this represents the controlsecretion), the catheter is removed and replaced with the pluggingscrew. The test drug is now administered orally in a volume of 2 mL/kgvia gastric intubation. Forty-five minutes later the plugging screw isagain removed, replaced with the catheter attached to a small plasticvial and another 2-hour sample is collected. The secretions in thesecond sample are compared to those of the control sample in order todetermine the effects of the test drug.

When test compounds are to be evaluated parenterally, the animal isinjected ip or sc with the test compound vehicle in a volume of 2 mL/kgimmediately after discarding the initial 60-minute collection. Atwo-hour sample is collected (control secretion) and the animals areinjected either ip or sc with the test compound in a volume of 2 mL/kg.An additional two-hour sample is collected and its secretions arecompared to those of the control period to determine drug effects.

The samples are centrifuged and placed in a graduated centrifuge tubefor volume determination. Titratable acidity is measured by titrating aone-mL sample to pH 7.0 with 0.02N NaOH, using an Autoburet and anelectrometric pH meter (Radiometer). Titratable acid output iscalculated in micro-equivalents by multiplying the volume in millilitersby the acid concentration in milliequivalents per liter.

Results are expressed as percent inhibition relative to controlreadings. Dose response curves are constructed and ED₅₀ values arecalculated by regression analyses. At least three rats are used at eachdosage level and a minimum of three dosage levels are utilized fordetermination of a dose response curve.

                  TABLE 1                                                         ______________________________________                                        Gastric Antisecretory Activity in the Gastric Fistula Rat                                 ED.sub.50 sc                                                                             Potency Ratio                                          Compound    μmoles/kg                                                                             (cimetidine = 1.0)                                     ______________________________________                                        cimetidine   3.48       1.0                                                                (1.68-5.75)*                                                     Example 1    0.094     37                                                                 (0.043-0.20)                                                      Example 2   0.77       4.5                                                                (0.45-1.4)                                                        Example 3   ˜0.5 ˜7                                               Example 4   0.18       20                                                                 (0.10-0.36)                                                       ______________________________________                                         *95% confidence limits                                                   

Histamine H₂ -Receptor Antagonism-Isolated Guinea Pig Atria Assay

Histamine produces concentration-related increases in the contractilerate of isolated, spontaneously beating guinea pig right atria. Black etal., Nature, 236, 385 (1972), described the receptors involved in thiseffect of histamine as histamine H₂ -receptors when they reported theproperties of burimamide, a competitive antagonist of these receptors.Subsequent investigations by Hughes and Coret, Proc. Soc. Exp. Biol.Med., 148, 127 (1975) and Verma and McNeill, J. Pharmacol. Exp. Ther.,200, 352 (1977) support the conclusion of Black and coworkers that thepositive chronotropic effect of histamine in isolated guinea pig rightatria is mediated via histamine H₂ -receptors. Black et al., Agents andActions, 3, 133 (1973) and Brimblecombe et al., Fed. Proc., 35, 1931(1976) have utilized isolated guinea pig right atria as a means forcomparing the activities of histamine H₂ -receptor antagonists. Thepresent comparative studies were carried out using a modification of theprocedure reported by Reinhardt et al., Agents and Actions, 4, 217(1974).

Male Hartley strain guinea pigs (350-450 gm) were sacrificed by a blowon the head. The heart was excised and placed in a Petri dish ofoxygenated (95% O₂, 5% CO₂) modified Krebs solution (g/liter: NaCl 6.6,KCl 0.35, MgSO₄.7H₂ O 0.295, KH₂ PO₄ 0.162, CaCl₂ 0.238, NaHCO₃ 2.1 anddextrose 2.09). The spontaneously beating right atrium was dissectedfree from other tissues and a silk thread (4-0) attached to each end.The atrium was suspended in a 20 ml muscle chamber containing oxygenatedmodified Krebs solution maintained at 32° C. Atrial contractions wererecorded isometrically by means of a Grass FT 0.03 force displacementtransducer and recordings of contractile force and rate were made with aBeckman RP Dynograph.

A resting tension of 1 g was applied to the atrium and it was allowed toequilibrate for 1 hour. At the end of the equilibration period asubmaximal concentration of histamine dihydrochloride (3×10⁻⁶ M) wasadded to the bath and washed out to prime the tissue. Histamine was thenadded to the bath in a cumulative fashion using 1/2 log 10 intervals togive final molar bath concentrations of 1×10⁻⁷ to 3×10⁻⁵. Thehistamine-induced increase in atrial rate was allowed to plateau beforethe next successive concentration was added. The maximal responseinvariably occurred at the 3×10⁻⁵ M concentration. The histamine waswashed out several times and the atrium allowed to return to controlrate. The test compound was then added at appropriate molarconcentrations and, after a 30-minute incubation, the histamine doseresponse was repeated adding higher concentrations as needed.

The dissociation constants (K_(B)) were derived from Schild plots by themethod of Arunlakshana, O. and Schild, H. O. [Br. J. Pharmacol. 14, 48(1959)] using at least three dose levels. Parallel shifts indose-response curves were obtained without depressing the maximalresponse at the antagonist concentrations utilized, and the results areshown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Activity in Isolated Guinea Pig Right Atria                                                                 Potency Ratio                                   Compound                                                                              N        K.sub.B (μmoles)                                                                        (cimetidine = 1.0)                              ______________________________________                                        cimetidine                                                                            20       0.41  (.21-.64)*                                                                           1.0                                             Example 1                                                                             12       0.003 (.001-.004)                                                                          137                                             Example 4                                                                             11       0.004 (.001-.010)                                                                          102                                             ______________________________________                                         *95% confidence limits                                                   

As described in U.S. patent application Ser. No. 475,985, filed Mar. 16,1983 by our colleague Thomas A. Montzka, the compounds of Formula I alsomay be prepared by ring closure of a compound of Formula II withN,N'-thiobisphthalimide having the formula ##STR29## The use ofN,N'-thiobisphthalimide instead of S₂ Cl₂ or SCl₂ for the ring closurereaction results in both purer and higher crude yields of the compoundsof Formula I. The crude products of Formula I thereby produced normallyare pure enough to form crystalline salts directly without priorchromatographic purification.

In this process, the starting diimidamide of Formula II is reacted withabout an equimolar amount of N,N'-thiobisphthalimide in an inert organicsolvent such as CH₂ Cl₂. Preferably the starting diimidamide is used inthe form of its trihydrochloride salt, in which case three molarequivalents of an amine, such as triethylamine, are added to thereaction mixture to neutralize the trihydrochloride salt. The reactionmay be conducted by stirring at room temperature for about an hour toinsure completeness of the reaction. The phthalimide which precipitatesfrom the reaction mixture is then extracted with a strong base (e.g.10-20% aqueous KOH), and the organic solvent layer is dried, filteredand concentrated to yield the crude compound of Formula I. TheN,N'-thiobisphthalimide used in the reaction is a known compound whichmay be prepared as described in the Canadian Journal of Chemistry, 44,2111-2113 (1966), or as described below in Preparation No. 1.

PREPARATION NO. 1 N,N'-Thiobisphthalimide

A cooled (0° C.) solution of phthalimide (14.7 g, 0.1 mole) in 80 ml ofdimethylformamide (DMF) was treated dropwise with sulfur dichloride(5.15 g, 0.05 mole). After the addition, the mixture was allowed to warmto 20° C. with stirring over four hours. The solid was collected anddried to give 12.5 g of the title compound as a DMF solvate, mp301°-315° C. Both ir and nmr spectra are consistent for structure.

Anal. Calc'd. for C₁₆ H₈ N₂ O₄ S.C₃ H₇ NO: C, 57.42; H, 3.80; N, 10.57;S, 8.07; Found: C, 57.50; H, 3.80; N, 1029; S, 8.57.

The DMF solvate can be removed by recrystallization of the abovematerial from chloroform; mp of the DMF-free product was 320°-325° C.The nmr spectrum shows that the DMF has been removed.

Anal. Calc'd. for C₁₆ H₈ N₂ O₄ S: C, 59.25; H, 2.49; N, 8.64; S, 9.89;Found: C, 59.21; H, 2.21; N, 8.91; S, 10.14.

EXAMPLE 13-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazoleA. N-[3-(3-Piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride

A suspension of3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide (17.1 g; 47.0 mmoles) [prepared according to published U.K.patent application No. 2,067,987] in 450 mL of methanol was treated with38 mL of concentrated HCl. The resultant solution was stirred for 3hours at ambient temperature. Concentration of the solution followed byazeotropic removal of water with absolute ethanol gave colorlesscrystals. These were suspended in 200 mL of absolute ethanol, filteredand dried under vacuum to give 16.6 g (82.6%) of the title compound,m.p. 205°-222° C. (dec.). Recrystallization from 50% methanol-ethylacetate gave an analytical sample, m.p. 206°-216° C. (dec.).

Anal. Calc'd for C₁₇ H₂₇ N₅ O.3HCl: C, 47.84; H, 7.08; N, 16.41; Found:C, 47.56; H, 7.18; N, 16.75.

B.3-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole

A stirred suspension ofN-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride (2.13 g, 5.0 mmoles) [prepared in Step A] in 20 mL ofdimethylformamide (DMF) was treated with sulfur monochloride (2.02 g,15.0 mmoles) and stirred for 4 hours. The resultant mixture was pouredcautiously into 200 mL of water and made basic with K₂ CO₃. This wasextracted with 3×50 mL portions of methylene chloride and, after dryingover MgSO₄ and concentration, 2.1 g of a dark gum containing the productwas obtained. The product was purified by preparative high pressureliquid chromatography on silica using CH₂ Cl₂ (100):2-propanol(10):NH₄OH(0.5) as the mobile phase. The appropriate fractions yielded 0.80 g ofthe title compound which gave, with fumaric acid in n-propanol, 0.76 g(21.4%) of the title compound as a crystalline fumarate salt, m.p.187°-187.5° C. HPLC indicated a purity of >99%.

Anal. Calc'd for (C₁₇ H₂₅ N₅ OS)₂.C₄ H₄ O₄ : C, 56.27; H, 6.71; N,17.27; S, 7.90; Found: C, 56.09; H, 6.36; N, 16.98; S, 8.08.

A portion of the fumarate was suspended in water, neutralized with K₂CO₃ and extracted with CH₂ Cl₂. The CH₂ Cl₂ was concentrated and thefree base of the title compound crystallized out; m.p. 43°-47° C. Aportion of the free base was converted to the hydrochloride salt, m.p.138°-140° C.

Anal. Calc'd. for C₁₇ H₂₅ N₅ OS.HCl: C, 53.18; H, 6.38; N, 18.24; S,8.35; Found: C, 53.14; H, 6.88; N, 18.49; S, 8.74.

EXAMPLE 23-Amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazoleA.N-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethyl}ethanediimidamidetrihydrochloride hydrate

A suspension of3-amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide (6.56 g; 20.0 mmoles) [prepared according to published U.K.patent application No. 2,067,987] in 200 mL of methanol was warmedslightly to achieve complete solution, then treated with 13.3 mL ofconcentrated HCl. After stirring at ambient temperature for 2.5 hours,the solution was concentrated and the residue was triturated with 70 mLof absolute ethanol. The crystals were collected by filtration and driedunder vacuum to give 4.3 g (52%) of the title compound, m.p. 166°-169°C. (dec.).

Anal. Calc'd for C₁₂ H₂₁ N₅ OS.3HCl.H₂ O: C, 35.08; H, 6.38; N, 17.05;S, 7.80; Found: C, 34.85; H, 6.24; N, 17.45; S, 7.97.

B.3-Amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole

To a stirred suspension ofN-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethyl}ethanediimidamidetrihydrochloride hydrate (12.3 g; 30.0 mmoles) [prepared in Step A] in150 mL of DMF was added 7.2 mL of sulfur monochloride (12.1 g; 90mmoles). After stirring for 4 hours at ambient temperature,approximately half of the DMF was removed at reduced pressure. Theremaining black solution was poured into 1 liter of water, made basicwith K₂ CO₃ and extracted first with ethyl acetate and then withchloroform. After drying over MgSO₄, filtration and concentration, 9.0 gof a black gum containing the product was obtained. This was purified bypreparative high pressure liquid chromatography on silica using ethylacetate(100):2-propanol(10):NH₄ OH(0.5) as the mobile phase. Theappropriate fractions yielded 1.24 g of the title compound as a gum.

Treatment of part of this product with an equivalent amount of 2N HCl inmethanol yielded the hydrochloride salt of the title compound.

Anal. Calc'd for C₁₂ H₁₉ N₅ S₂ O.HCl: C, 41.18; H, 5.76; N, 20.02; S,18.33; Found (corr. for 1.65% H₂ O): C, 40.54; H, 5.70; N, 19.39; S,18.44.

Treatment of the product with an equivalent amount of cyclohexylsulfamicacid in acetone yielded the cyclohexylsulfamate salt of the titlecompound, m.p. 93°-95° C.

Anal. Calc'd for C₁₂ H₁₉ N₅ S₂ O.C₆ H₁₃ NO₃ S: C, 43.88; H, 6.55; N,17.06; S, 19.53; Found: C, 43.77; H, 6.17; N, 17.21; S, 19.58.

EXAMPLE 33-Amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazoleA.N-{2-[(5-Dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethyl}ethanediimidamidetrihydrochloride

A stirred solution of3-amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide (17.9 g, 50.0 mmoles) [prepared according to the generalprocedure described in published U.K. patent application No. 2,067,987]in 500 mL of methanol was treated with 33.3 mL of concentrated HCl.After stirring for 3 hours, the reaction mixture was concentrated andexcess water was removed by azeotropic concentration with absoluteethanol to give an almost colorless crystalline residue. The residue wastriturated with 200 mL of absolute ethanol at 0° C., filtered and driedto give 16.9 g (80%) of the title compound, m.p. 206°-220° C. (dec.).Recrystallization from 50% methanol-ethyl acetate gave a product havingm.p. 210°-221° C. (dec.).

Anal. Calc'd for C₁₃ H₂₃ N₅ S₂.3HCl: C, 36.92; H, 6.20; N, 16.56; S,15.17; Found: C, 36.76; H, 6.33; N, 16.97; S, 15.54.

B.3-Amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole

To a stirred suspension ofN-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethyl}ethanediimidamidetrihydrochloride (6.34 g; 15.0 mmoles) [prepared in Step A] in 60 mL ofDMF was added 6.1 g (45.0 mmoles) of sulfur monochloride. After stirringfor 4 hours at ambient temperature, the reaction mixture was poured into800 mL of water, made basic with K₂ CO₃, and extracted several timeswith 100 mL-portions of methylene chloride. The extracts were dried overMgSO₄, filtered, and concentrated to give 3.4 g of a black gumcontaining the product. The product was purified by preparative highpressure liquid chromatography on silica using CH₂ Cl₂(100):2-propanol(10):NH₄ OH(0.5) as the mobile phase. Furtherpurification was achieved by an additional preparative high pressureliquid chromatography on silica using CH₂ Cl₂ (100):CH₃ OH(2.5):NH₄OH(0.5) as the mobile phase. The appropriate fractions yielded the titlecompound (purity ˜98%). Treatment of the product with an equivalentamount of 2N HCl gave the hydrochloride salt of the title compound.

Anal. Calc'd for C₁₃ H₂₁ N₅ S₃.HCl: C, 41.09; H, 5.84; N, 18.43; S,25.32; Found (corr. for 0.51% H₂ O): C, 40.78; H, 5.63; N, 18.31; S,25.44.

EXAMPLE 43-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazoleA. N-[3-(3-Pyrrolidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride

A suspension of3-amino-4-[3-(3-pyrrolidinomethylphenoxypropylamino]-1,2,5-thiadiazole1-oxide (13.4 g; 38.3 mmoles) [prepared according to published U.K.patent application No. 2,067,987] in 350 mL of methanol was treated with25.5 mL of concentrated HCl. The resultant solution was stirred for 3hours at ambient temperature. Concentration of the solution followed byazeotropic removal of water with absolute ethanol gave the product. Thecrystalline residue was triturated with 150 mL of absolute ethanol,filtered and dried to give 10.8 g of the title compound, m.p. 195°-203°C. (dec.).

Anal. Calc'd for C₁₆ H₂₅ H₅ O.3HCl: C, 46.55; H, 6.84; N, 16.97; Found:C, 46.55; H, 6.93; N, 16.93.

B.3-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole

A stirred suspension ofN-[3-(3-pyrrlidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride (8.25 g; 20.0 mmoles) [prepared in Step A] in 80 mL ofDMF was treated with sulfur monochloride (5.4 g; 40.0 mmoles) andstirred under a nitrogen atmosphere for 3 hours. Concentration of thereaction mixture gave a dark gum which was suspended in 500 mL of water,made basic with K₂ CO₃ and extracted with 3×100 mL of methylenechloride. The extracts were dried over MgSO₄, filtered and concentratedto give 7.5 g of a dark gum containing the product. The product waspurified by preparative high pressure liquid chromatography on silicausing CH₂ Cl₂ (100):2-propanol(5):NH₄ OH(0.5) as the mobile phase.Fractions containing the desired product were combined and concentratedto give 1.64 g (24.6%) of the purified title product. Treatment of theproduct in absolute ethanol with an equivalent amount of 2N HCl gave thehydrochloride salt of the title compound (1.13 g); m.p. 138°-140° C.

Anal. Calc'd for C₁₆ H₂₃ N₅ OS.HCl: C, 51.95; H, 6.54; N, 18.93; S,8.67; Found: C, 51.97; H, 6.36; N, 18.63; S, 8.76.

EXAMPLE 5

The general procedure of Example 1, Steps A and B, is repeated exceptthat the3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide utilized therein is replaced by an equimolar amount of

(a)3-amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(b)3-amino-4-[3-(3-diethylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(c)3-amino-4-{3-[3-(2-methylpyrrolidino)methylphenoxy]propylamino}-1,2,5-thiadiazole1-oxide,

(d)3-amino-4-{3-[3-(3-methylpyrrolidino)methylphenoxy]propylamino}-1,2,5-thiadiazole1-oxide,

(e)3-amino-4-{3-[3-(4-methylpiperidino)methylphenoxy]propylamino}-1,2,5-thiadiazole1-oxide,

(f)3-amino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(g)3-amino-4-{3-[3-(N-methylpiperazino)methylphenoxy]propylamino}-1,2,5-thiadiazole1-oxide,

(h)3-amino-4-[3-(3-diallylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(i)3-amino-4-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(j)3-amino-4-[3-(3-heptamethyleneiminomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(k)3-amino-4-{3-[3-(3-azabicyclo[3.2.2]non-3-yl)methylphenoxy]propylamino}-1,2,5-thiadiazole1-oxide and

(l)3-amino-4-{3-[3-(3-pyrrolino)methylphenoxy]propylamino}-1,2,5-thiadiazole1-oxide, respectively.

and there is thereby produced

(a)3-amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(b)3-amino-4-[3-(3-diethylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(c)3-amino-4-{3-[3-(2-methylpyrrolidino)methylphenoxy]propylamino}-1,2,5-thiadiazole,

(d)3-amino-4-{3-[3-(3-methylpyrrolidino)methylphenoxy]propylamino}-1,3,5-thiadiazole,

(e)3-amino-4-{3-[3-(4-methylpiperidino)methylphenoxy]propylamino}-1,2,5-thiadiazole,

(f)3-amino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(g)3-amino-4-{3-[3-(N-methylpiperazino)methylphenoxy]propylamino}-1,2,5-thiadiazole,

(h)3-amino-4-[3-(3-diallylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(i)3-amino-4-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(j)3-amino-4-[3-(3-heptamethyleneiminomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(k)3-amino-4-{3-[3-(3-azabicyclo[3.2.2.]non-3-yl)methylphenoxy]propylamino}-1,2,5-thiadiazoleand

(l)3-amino-4-{3-[3-(3-pyrrolino)methylphenoxy]propylamino}-1,2,5-thiadiazole,respectively.

EXAMPLE 63-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole

This is a variation of Example 1, Step B, utilizing less sulfurmonochloride and a shorter reaction time.

To a stirred suspension ofN-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride (12.08 g; 28.3 mmoles) in 120 mL of DMF was addedsulfur monochloride (7.64 g; 56.6 mmoles) and the mixture was stirredunder an N₂ atmosphere for 3 hours. The DMF was removed at reducedpressure to leave a black gum which was suspended in water, made basicwith K₂ CO₃ and extracted with 3×100 mL portions of CH₂ Cl₂. Thecombined extracts were dried over MgSO₄, filtered and concentrated to ablack gum. This gum was purified by preparative high pressure liquidchromatography on silica using CH₂ Cl₂ (100):2-propanol(5):NH₄ OH(0.5)as the mobile phase. The appropriate fractions yielded 3.1 g of thetitle product as a dark oil which gave, with fumaric acid in n-propanol,2.66 g (23.2%) of the title compound as a crystalline fumarate salt,m.p. 186°-186.5° C. HPLC indicated a purity of 99%.

Anal. Calc'd. for (C₁₇ H₂₅ N₅ OS)₂.C₄ H₄ O₄ : C, 56.27; H, 6.71; N,17.27; S, 7.90; Found: C, 56.27; H, 6.96; N, 17.31; S, 7.98.

EXAMPLE 73-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole

This is a variation of Example 1, Step B, utilizing sulfur dichlorideinstead of sulfur monochloride.

To a stirred suspension ofN-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride (854 mg; 2 mmoles) in 6 mL of DMF under N₂ in an icebath was added SCl₂ (206 mg; 2 mmoles) in 2 mL of DMF. The reactionmixture was stirred at ambient temperature and the title compound wasproduced.

EXAMPLE 83-Methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazolA. N-Methyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride

A suspension of3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide (4.13 g; 10.9 mmoles) [prepared according to published U.K.patent application No. 2,067,987] in 95 ml of methanol was treated with7.2 ml of concentrated HCl. After stirring at ambient temperature for 3hours, the solution was concentrated and the residue was triturated withacetone, filtered and dried to give 4.35 g (90.4%) of product. A samplewas recrystallized from aqueous isopropyl alcohol to give the titlecompound, mp 207°-225° C. (dec.).

Anal. Calc'd. for C₁₈ H₂₉ N₅ O.3HCl: C, 49.03; H, 7.33; N, 15.89; Found(corr. for 0.94% H₂ O): C, 49.37; H, 7.35; N, 15.71.

B.3-Methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole

A mixture ofN-methyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride (3.74 g; 8.47 mmoles) [prepared in Step A], 34 ml ofCH₂ Cl₂ and 3.5 ml of triethylamine was treated withN,N'-thiobisphthalimide (DMF solvate) (3.36 g; 8.46 mmoles) and stirredfor one hour. The mixture was washed with 30 ml of 10% KOH, dried(MgSO₄), filtered, diluted with toluene and concentrated to give 3.6 gof the product. The product was purified by flash chromatography on 90 gof silica gel (230-400 mesh) using ethyl acetate-methanol (95:5) as theeluent to give 1.9 g (62%) of the title compound. Treatment of theproduct with an equivalent amount of aqueous HCl in 1-propanol gave thehydrochloride salt of the title compound, mp 163.5°-164.5° C.

Anal. Calc'd. for C₁₈ H₂₇ N₅ OS.HCl: C, 54.32; H, 7.04; N, 17.60; S,8.06; Cl, 8.91; Found: C, 54.35; H, 7.07; N, 17.64; S, 8.36; Cl, 8.86.

EXAMPLE 93-Benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazoleA. N-Benzyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride

A suspension of3-benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide (5.14 g; 11.3 mmoles) [prepared according to published U.K.patent application No. 2,067,987] in 100 ml of methanol was treated with7.55 ml of concentrated HCl. After stirring at ambient temperature for 3hours, the solution was concentrated and the residue was triturated withacetone, filtered and dried to give 5.16 g (88%) of the title compound,mp 187°-205° C. (dec.).

Anal. Calc'd. for C₂₄ H₃₃ N₅ O.3HCl: C, 55.75; H, 7.03; N, 13.55; Cl,20.57; Found: C, 54.88; H, 6.75; N, 13.33; Cl, 20.20.

B.3-Benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole

A mixture ofN-benzyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride (4.73 g; 9.16 mmoles) [prepared in Step A], 45 ml ofCH₂ Cl₂ and 3.8 ml of triethylamine was treated withN,N'-thiobisphthalimide (DMF solvate) (3.64 g; 9.16 mmoles) and stirredfor one hour. The mixture was washed with 44 ml of 10% KOH, dried(MgSO₄), filtered, diluted with toluene and concentrated. The residuewas chromatographed by flash chromatography on 110 g of silica gel(230-400 mesh) using ethyl acetate as the eluent to give 3.1 g (77%) ofthe title compound. Treatment of the product with an equivalent amountof aqueous HCl in 2-propanol gave the hydrochloride salt of the titlecompound, mp 138°-141° C.

Anal. Calc'd. for C₂₄ H₃₁ N₅ OS.HCl: C, 60.80; H, 6.80; N, 14.77; S,6.76; Cl, 7.48; Found: C, 60,53; H, 6.64; N, 14.99; S, 6.91; Cl, 7.47.

EXAMPLE 103-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole

This is a variation of Example 1, Step B, utilizingN,N'-thiobisphthalimide instead of sulfur monochloride.

A mixture of N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride (27.3 g; 64.0 mmoles) [prepared in Example 1, Step A],250 ml of CH₂ Cl₂ and 26.6 ml (192.0 mmoles) of triethylamine wastreated portionwise with N,N'-thiobisphthalimide (DMF solvate) (25.4 g;64.0 mmoles). After stirring at ambient temperature for one hour, themixture was washed with 120 ml of 20% KOH, dried (MgSO₄), filtered andconcentrated, then taken up in 150 ml of toluene and reconcentrated. Theproduct was taken up in 250 ml of 1-propanol and 10.7 ml of 6N HCl,treated with decolorizing carbon and filtered through Celite. Thissolution was concentrated to 100 ml volume, diluted with 175 ml of dry1-propanol and stored at 0° C. to give 20.2 g (82.1%) of crystallinehydrochloride salt of the title compound, mp 137°-138° C.

Anal. Calc'd. for C₁₇ H₂₅ N₅ OS.HCl: C, 53.18; H, 6.83; N, 18.24; S,8.35; Found: C, 52.78; H, 6.74; N, 18.52; S, 8.66.

EXAMPLE 113-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole

This is a variation of Example 4, Step B, utilizingN,N'-thiobisphthalimide instead of sulfur monochloride.

A mixture of N-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride (22.0 g; 53.0 mmoles) [prepared in Example 4, Step A],200 ml of CH₂ Cl₂ and 22 ml of triethylamine was treated withN,N'-thiobisphthalimide (DMF solvate) (21.2 g; 53.0 mmoles). Afterstirring at ambient temperature for one hour, the mixture was washedwith 100 ml of 20% KOH, dried (MgSO₄), filtered, diluted with 100 ml oftoluene and concentrated. The product was treated with one equivalent ofaqueous HCl in 1-propanol to give 13.2 g (67%) of the hydrochloride saltof the title compound, mp 135°-137° C.

Anal. Calc'd. for C₁₆ H₂₃ N₅ OS.HCl: C, 51.95; H, 6.54; N, 18.93; S,8.67; Found: C, 51.92; H, 6.55; N, 19.30; S, 9.06.

EXAMPLE 123-Amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazoleA.N-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethyl}ethanediimidamidetrihydrochloride

A suspension of3-amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide (7.8 g; 22.6 mmoles) [prepared according to published U.K.patent application No. 2,067,987] in 150 ml of methanol was treated with15.0 ml of concentrated HCl. After stirring at ambient temperature for 3hours, the solution was concentrated and the residue triturated with1-propanol, filtered and dried to give 7.38 g (80%) of product. A samplewas recrystallized from methanol-acetone to give the title compound, mp190°-205° C. (dec.).

Anal. Calc'd. for C₁₂ N₂₁ N₅ S₂.3HCl: C, 35.25; H, 5.92; N, 17.13;Found: C, 35.03; H, 5.93; N, 17.39.

B.3-Amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole

A mixture ofN-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethyl}ethanediimidamidetrihydrochloride (6.13 g; 15.0 mmoles) [prepared in Step A], 60 ml ofCH₂ Cl₂ and 6.3 ml of triethylamine was treated withN,N'-thiobisphthalimide (DMF solvate) (5.96 g; 15.0 mmoles) and stirredfor one hour. The mixture was washed with 100 ml of 10% KOH, dried(MgSO₄), filtered, diluted with toluene and concentrated to give 5.1 gof product. Treatment of the product with 0.5 molar equivalent offumaric acid in 1-propanol gave the fumaric acid salt of the compound,mp 141°-143° C. The nmr spectrum in DMSO-d₆ shows the presence ofapproximately 0.12 moles of 1-propanol.

Anal. Calc'd. for (C₁₂ H₁₉ N₅ S₃)₂.C₄ H₄ O₄.0.12C₃ H₈ O: C, 43.68; H,5.61; N, 17.75; S, 24.38; Found: C, 43.41; H, 5.53; N, 17.54; S, 24.24.

EXAMPLE 133-Amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazoleA.N-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethyl}ethanediimidamidetrihydrochloride

A suspension of3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide (6.1 g; 15.8 mmoles) [prepared according to published U.K.patent application No. 2,067,987] in 80 ml of methanol was treated with10.5 ml of concentrated HCl. After stirring at ambient temperature for 3hours, the solution was concentrated and the residue triturated with 50ml of 1-propanol, filtered and dried to give 5.86 g (83%) of product. Asample was recrystallized from methanol-acetone to give the titlecompound, mp 201°-214° C. (dec.).

Anal. Calc'd. for C₁₅ H₂₅ N₅ S₂.3HCl: C, 40.13; H, 6.29; N, 15.60; S,14.29; Found: C, 39.97; H, 6.47; N, 15.28; S, 14.63.

B.3-Amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole

A mixture ofN-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethyl}ethanediimidamidetrihydrochloride (5.17 g; 11.5 mmoles) [prepared in Step A], 48 ml ofCH₂ Cl₂ and 4.8 ml of triethylamine was treated withN,N'-thiobisphthalimide (DMF solvate) (4.57 g; 11.5 mmoles) and stirredfor one hour. The mixture was washed with 90 ml of 10% KOH, dried(MgSO₄), filtered, diluted with toluene and concentrated to give 4.5 gof product. Treatment of the product with one equivalent of cyclohexylsulfamic acid in methanol gave the cyclohexyl sulfamate salt of thetitle compound, mp 142°-143° C.

Anal. Calc'd. for C₁₅ H₂₃ N₅ S₃.C₆ H₁₃ NO₃ S: C, 45.96; H, 6.61; N,15.31; S, 23.38; Found: C, 45.61; H, 6.41; N, 15.46; S, 23.48.

EXAMPLE 14

The general procedures of Example 1, Step A, and then either Example 1,Step B, or Example 10 is repeated except that the3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide utilized therein is replaced by an equimolar amount of

(a)3-ethylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(b)3-allylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(c)3-(2-propynyl)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(d)3-(3-pyridylmethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(e)3-(6-methyl-3-pyridyl)methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide and

(f)3-(3,4-methylenedioxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide, respectively,

and there is thereby produced

(a)3-ethylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(b)3-allylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(c)3-(2-propynyl)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(d)3-(3-pyridylmethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole,

(e)3-(6-methyl-3-pyridyl)methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazoleand

(f)3-(3,4-methylenedioxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole,respectively.

EXAMPLE 153-Amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazoleA.3-Amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole1-oxide

A solution of 3-(6-piperidinomethyl-2-pyridyloxy)propylamine (4.65 g;18.6 mmoles) [prepared according to published U.K. patent applicationNo. 2,098,988] in 50 ml of methanol was reacted with3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.74 g; 18.6 mmoles)according to the general procedure described in U.K. patent applicationNo. 2,067,987 to give a solution containing3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole1-oxide. A purified sample melted at 145°-147° C.

B. N-[3-(6-Piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamidetrihydrochloride

A methanolic solution of the product prepared in Step A was diluted to100 ml and 12.4 ml of concentrated HCl was added. The solution wasstirred at ambient temperature for 18 hours, concentrated, and theresidue was dissolve in 80 ml of water and extracted twice with CH₂ Cl₂.The aqueous layer was concentrated, treated with n-propanol andconcentrated under high vacuum to give the title compound as a foam.

C.3-Amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole

A mixture of the crude product prepared in Step B in 80 ml of CH₂ Cl₂and containing 7.69 ml of triethylamine was treated withN,N'-thiobisphthalimide (DMF solvate) (7.35 A g; 18.5 mmoles). Afterstirring at ambient temperature for one hour, the mixture was washedwith 50 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried(Na₂ SO₄), filtered and evaporated under reduced pressure to give thecrude product. The product was purified by flash chromatography on 100 gof silica gel (230-400 mesh) using ethyl acetate-methanol (95:5) as theeluent to give 3.63 g of the title compound as a viscous oil. Treatmentof the product with one equivalent of cyclohexyl sulfamic acid inacetone gave the cyclohexyl sulfamate salt of the title compound, mp125.5°-131° C.

Anal. Calc'd. for C₁₆ H₂₄ N₆ OSC₆ H₁₃ NO₃ S: C, 50.07; H, 7.07; N,18.58; S, 12.15; Found: C, 50.02; H, 7.03; N, 18.54; S, 12.14.

EXAMPLE 163-Amino-4-[3-(6-dimethylaminomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole

When a methanolic solution of3-(6-dimethylaminomethyl-2-pyridyloxy)propylamine [prepared according topublished U.K. patent application No. 2,098,988] is reacted with3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide according to the generalprocedure described in U.K. patent application No. 2,067,987 and theresulting3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole1-oxide is successively reacted by the general procedure described inExample 1, Step A, and then by either Example 1, Step B, or Example 10,the title compound is thereby produced.

EXAMPLE 173-Amino-4-{2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole

When a suspension of3-amino-4-{2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide [prepared according to published U.K. patent application No.2,067,987] is successively reacted according to the procedures ofExample 1, Step A, and then by either Example 1, Step B, or Example 10,the title compound is thereby produced.

EXAMPLE 183-Amino-4-{2-[(6-piperidinomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole

When a suspension of3-amino-4-{2-[(6-piperidinomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide [prepared according to published U.K. patent application No.2,067,987] is successively reacted according to the procedures ofExample 1, Step A, and then by either Example 1, Step B, or Example 10,the title compound is thereby produced.

EXAMPLE 19

The general procedure of Example 1, Step A, and then either Example 1,Step B, or Example 10 is repeated except that the3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1oxide utilized therein is replaced by an equimolar amount of

(a)3-amino-4-[3-(3-piperidinomethylthiophenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(b)3-amino-4-[3-(3-dimethylaminomethylthiophenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(c)3-amino-4-[3-(3-pyrrolidinomethylthiophenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(d)3-amino-4-[3-(4-dimethylaminomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole1-oxide,

(e)3-amino-4-[3-(5-dimethylaminomethyl-3-thienyloxy)propylamino]-1,2,5-thiadiazole1-oxide,

(f)3-amino-4-[3-(5-piperidinomethyl-3-thienyloxy)propylamino]-1,2,5-thiadiazole1-oxide,

(g)3-amino-4-{2-[(4-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide and

(h)3-amino-4-{2-[(4-piperidinomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide, respectively,

and there is thereby produced

(a)3-amino-4-[3-(3-piperidinomethylthiophenoxy)propylamino]-1,2,5-thiadiazole

(b)3-amino-4-[3-(3-dimethylaminomethylthiophenoxy)propylamino]-1,2,5-thiadiazole,

(c)3-amino-4-[3-(3-pyrrolidinomethylthiophenoxy)propylamino]-1,2,5-thiadiazole,

(d)3-amino-4-[3-(4-dimethylaminomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole,

(e)3-amino-4-[3-(5-dimethylaminomethyl-3-thienyloxy)propylamino]-1,2,5-thiadiazole,

(f)3-amino-4-[3-(5-piperidinomethyl-3-thienyloxy)propylamino]-1,2,5-thiadiazole,

(g)3-amino-4-{2-[(4-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazoleand

(h)3-amino-4-{2-[(4-piperidinomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole,respectively.

The above starting materials are prepared according to the generalprocedures described in published U.K. patent application No. 2,067,987.The precursors of the starting materials are prepared by the proceduresand analogous general procedures described in U.K. patent applicationNos. 2,067,987, 2,098,988, 2,063,875 and published European patentapplication No. 49,173.

EXAMPLE 203-Amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazoleA. 3-(4-Piperidinomethyl-2-pyridyloxy)propylamine

When the general procedure for the preparation of3-(6-piperidinomethyl-2-pyridyloxy)propylamine described in U.K. patentapplication No. 2,098,988 was followed except that the2-chloro-6-methylpyridine utilized therein was replaced by2-bromo-4-methylpyridine, then the title compound was produced as anoil.

Anal. Calc'd. for C₁₄ H₂₃ N₃ O: C, 67.44; H, 9.30; N, 16.8; Found: C,67.54; H, 8.98; N, 16.55.

B.3-Amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole1-oxide

A solution of the product of Step A (6.5 g; 26.0 mmoles) in 90 ml ofmethanol was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide(3.84 g; 26.0 mmoles) according to the general procedures described inU.K. patent application No. 2,067,987 to give 6.33 g of product.Recrystallization from methanolacetonitrile yielded the title compound,mp 154°-158° C.

Anal. Calc'd. for C₁₆ H₂₄ N₆ OS: C, 52.73; H, 6.64; N, 23.06; S, 8.80;Found: C, 52.72; H, 6.30; N, 23.32; S, 8.74.

C. N-[3-(4-Piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamidetrihydrochloride

The product of Step B (5.0 g; 13.7 mmoles) was dissolved in 80 ml ofmethanol and treated with 9.1 ml of concentrated HCl. After stirring atambient temperature for 4.5 hours, the solution was evaporated todryness under reduced pressure to give the title compound.

D.3-Amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole

A mixture of the product prepared in Step C in 50 ml of CH₂ Cl₂ and 5.7ml of triethylamine was treated with N,N'-thiobisphthalimide (DMFsolvate) (5.44 g; 13.7 mmoles). After stirring at ambient temperaturefor one hour, the mixture was washed with 40 ml of 4N NaOH, water,saturated aqueous NaCl solution, dried (Na₂ SO₄), filtered andevaporated under reduced pressure to give the crude product. The productwas purified by flash chromatography on 90 g of silica gel (230-400mesh) using ethyl acetate-methanol (96:4) as the eluent to give 3.44 gof the title compound as a viscous oil. Treatment of the product withone equivalent of cyclohexyl sulfamic acid in acetone gave thecyclohexyl sulfamate of the title compound, mp 124.5°-126° C.

Anal. Calc'd. for C₁₆ H₂₄ N₆ OS.C₆ H₁₃ NO₃ S: C, 50.07; H, 7.07; N,18.58; S, 12.15; Found: C, 50.47; H, 7.12; N, 18.33; S, 11.87.

EXAMPLE 213Amino-4-{3-[3-(1,2,3,6-tetrahydro-1-pyridyl)methylphenoxy]propylamino}-1,2,5-thiadiazole

The general procedure of Example 15 was repeated, except that the3-(6-piperidinomethyl-2-pyridyloxy)propylamine utilized therein wasreplaced by an equivalent amount of3-[3-(1,2,3,6-tetrahydro-1-pyridyl)methylphenoxy]propylamine, to give2.31 g of product. Crystallization from toluene yielded the titlecompound, mp 99.5°-104° C.

Anal. Calc'd. for C₁₇ N₂₃ N₅ OS: C, 59.10; H, 6.71; N, 20.27; S, 9.28;Found (corr. for 2.19% H₂ O): C, 58.78; H, 6.71; N, 19.90; S, 9.26.

We claim:
 1. A compound of the formula ##STR30## wherein R¹ is hydrogen,(lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl,##STR31## in which p is 1 or 2, R² and R³ each are independentlyhydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when R² ishydrogen, R³ also may be trifluoromethyl, or R² and R³, taken together,may be methylenedioxy, and R⁴ is hydrogen, (lower)alkyl or(lower)alkoxy;m is an integer of from 0 to 2 inclusive; n is integer offrom 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and A is##STR32## in which R⁵ is hydrogen, (lower)alkyl or (lower)alkoxy, q isan integer of from 1 to 4 inclusive and R⁶ and R⁷ each are independently(lower)alkyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxymoiety is at least two carbon atoms removed from the nitrogen atom, orphenyl(lower)alkyl, and, when R⁶ is hydrogen, R⁷ also may becyclo(lower)alkyl, or R⁶ and R⁷, taken together with the nitrogen atomto which they are attached, may be pyrrolidino, methylpyrrolidino,dimethylpyrrolidino, morpholino, thiomorpholino, piperidino,methylpiperidino, dimethylpiperidino, N-methylpiperazino,1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino,octamethyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3pyrrolino; or anontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.2. A compound of claim 1 having the formula ##STR33## wherein R¹ ishydrogen or (lower)alkyl, m is 0 or 1, n is 2 or 3, Z is oxygen orsulfur and A is ##STR34## in which R⁵ is hydrogen or methyl, and R⁶ andR⁷ each are independently methyl or ethyl, or when taken together withthe nitrogen to which they are attached, R⁶ and R⁷ represent apyrrolidino or piperidino ring; or a nontoxic pharamaceuticallyacceptable salt, hydrate or solvate thereof.
 3. A compound of claim 1having the formula ##STR35## wherein R¹ and R⁵ each are independentlyhydrogen or methyl, and R⁶ and R⁷ each are independently methyl orethyl, or, when taken together with the nitrogen to which they areattached, R⁶ and R⁷ represent piperidino; or a nontoxic pharmaceuticallyacceptable salt, hydrate or solvate thereof.
 4. The compound of claim 1which is3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole,or a nontoxic pharmaceutically acceptable salt, hydrate or solvatethereof.
 5. The compound of claim 1 which is3-amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole,or a nontoxic pharmaceutically acceptable salt, hydrate or solvatethereof.